Disruptions in synaptic transmission underlie the symptoms of Alzheimer's disease patients, namely memory and cognitive deficits. Both neuronal cell death and synaptic dysfunction, independent of cell death, appear to be responsible for these deficits. Amyloid-p (A3) peptide, the primary constituent of neuritic plaques, has been shown to depress synaptic transmission in several models of disease. The objective of this application is to determine the precise types and conformations of A[unreadable] that mediate these alterations in neurotransmission, as well as mechanisms by which they act. Specific conformations of naturally-produced A[unreadable] will be isolated from cell lines, as well as from human AD brain tissue since this most closely mimics the types of A[unreadable] that are present within the disease state. The rationale for this proposal is that an understanding of how A[unreadable] contributes to neuronal dysfunction could lead to identification of better ways to diagnose the disease, as well as lead to potential targets for therapeutic intervention. In preliminary data, we demonstrate that A[unreadable] can alter synaptic transmission, likely through both presynaptic and postsynaptic mechanisms. We also show that synaptic activity can regulate release of A[unreadable] from neurons into the extracellular space. Together, this suggests that synaptically-released A[unreadable] may feedback to depress neuronal function. We propose to study the effect and mechanisms of A[unreadable] on synaptic activity using electrophysiology and live-cell imaging in primary neuronal cultures and acute brain slices, as well as a limited series of studies in vivo. The proposed training in electrophysiology and imaging will greatly enhance the career development of the applicant, allowing him to study synaptic transmission from many perspectives. Importantly, the scientific and technical expertise gained in the course of these studies will allow the candidate to attain his long-term goal of establishing an independent research career in neuroscience. Short description. Disruptions in synaptic transmission underlie many of the symptoms of Alzheimer's disease patients. This proposal will determine how naturally-produced A[unreadable], a key factor in Alzheimer's disease pathogenesis and progression, affects synaptic transmission. Understanding the causes of synaptic dysfunction may provide new avenues for diagnosis and treatment of the disease.